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SPECIES DIFFERENCES IN METABOLISM AND PHARMACOKINETICS OF A SPHINGOSINE-1-PHOSPHATE RECEPTOR AGONIST IN RATS AND DOGS: FORMATION OF A UNIQUE GLUTATHIONE ADDUCT IN THE RAT
- Source :
- Drug Metabolism and Disposition; August 2006, Vol. 34 Issue: 8 p1367-1375, 9p
- Publication Year :
- 2006
-
Abstract
- The pharmacokinetics and metabolism of 1-(4-((4-phenyl-5-trifluoromethyl-2-thienyl)methoxy)benzyl)azetidine-3-carboxylic acid (MRL-A), a selective agonist for the sphingosine-1-phosphate 1 (S1P1) receptor, were investigated in rats and dogs. In both species, more than 50% of the dose was excreted in bile. Specific to the rat, and observed in bile, were a taurine conjugate of MRL-A and a glucuronide conjugate of an azetidine lactam metabolite. In dogs, a smaller portion of the dose (54% of administered dose) was excreted intact in bile, and the major metabolites detected were an azetidine N-oxide of MRL-A and an acylglucuronide of an N-dealkylation product. This latter metabolite was also observed in rat bile. Stereoselective formation of the N-oxide isomer was observed in dogs, whereas the rat produced comparable amounts of both isomers. The formation of a unique glutathione adduct was observed in rat bile, which was proposed to occur via N-dealkylation, followed by reduction of the putative aldehyde product to form the alcohol, and dehydration of the alcohol to generate a reactive quinone methide intermediate. Incubation of a synthetic standard of this alcohol in rat microsomes fortified with reduced glutathione or rat hepatocytes resulted in formation of this unique glutathione adduct.
Details
- Language :
- English
- ISSN :
- 00909556 and 1521009X
- Volume :
- 34
- Issue :
- 8
- Database :
- Supplemental Index
- Journal :
- Drug Metabolism and Disposition
- Publication Type :
- Periodical
- Accession number :
- ejs9514351